This protocol is designed to study the natural history and epidemiology of hepatitis C virus (HCV) infection in an asymptomatic blood donor population found to be anti-HCV positive at the time of blood donation. Thus far, 683 subjects have been enrolled, including 402 RIBA positives, 145 RIBA indeterminates, and 112 RIBA negative controls. The early data have been published (N Engl J Med 334; 1691, 1996) and the trends have remained the same over time. The data can be summarized as follows: 1) characteristics of HCV-infected donors as compared with controls were a younger age, African-American race, and a lower education level; 2) independently associated risk factors for HCV were transfusion, intravenous drug use (IVDU), cocaine snorting, sexual promiscuity, and ear piercing among males; 3) although it was anticipated that IVDU would be a risk factor, it was a major surprise to find that 42% of RIB A-positive volunteer blood donors admitted to having used intravenous drugs at some point in their lives, generally 10 or more years before the donation; 4) another major surprise was the strong independent association between cocaine snorting and HCV positivity; we postulate that shared paraphernalia for snorting accompanied by frequent cocaine related epistaxis may serve as a covert vehicle for parenteral viral transmission; 5) 86% of RIBA positive donors were viremic, confirming the persistent nature of this agent; 6) in contrast, 13% of subjects appeared to have recovered from HCV infection as evidenced by repeatedly negative polymerase chain reaction for HCV RNA and by persistently normal alanine transaminase; 7) 66% had biochemical evidence of liver disease and 86% of those biopsied had an abnormal liver histology; however, only 6% had a severe histologic lesion despite prolonged infection (mean 18 years); and 8) despite an association with promiscuous sex practices, when we tested the direct partners of HCV-infected individuals, we could find no evidence for sexual transmission.